The World Journal of Biological Psychiatry

13/11/2020

New issue alert, issue 9 is now available online: https://www.tandfonline.com/toc/iwbp20/21/9?nav=tocList

Attention Deficit Hyperactivity disorder (ADHD) is characterised by inattention, hyperactivity, and impulsivity, and found in 5–10% of children and adolescents. Severe cases often also have learning difficulties and/or autism. ADHD also increases the risk of many other problems including Oppositional Defiant Disorder/Conduct Disorder (ODD/CD), anxiety states, substance misuse, crime and violence. The severity of ADHD and these risks are reduced by treatment with stimulant medication.

All too often ADHD is under-diagnosed, under-treated and sets young people on an adverse developmental trajectory that blights their lives. A diagnostic test or a means of predicting treatment response could go a long way to avoiding this. Several papers in this edition of the WJBP shed light on the pathophysiology of ADHD and related conditions. Taken together with other recent contributions in this journal and others, it is clear that progress is being made in elucidating their underlying neurobiology, but much less clear how that will translate into benefits for patients.
Brain structure and function

As part of the Enhancing NeuroImaging and Genetics through Meta-Analysis (ENIGMA) consortium, Hoogman et al. (2017) combined data from 1713 participants with ADHD and 1529 controls from 23 sites (median age 14, range 4–63 years) and found reduced volumes in ADHD in several brain regions, including the amygdala (Cohen’s d = –0.19), accumbens (d = –0.15), putamen (d = –0.14), caudate (d = –0.11), hippocampus (d = –0.11), and intracranial volume (d = –0.10). The effect sizes were highest in children, but symptom scores or stimulant medication use did not influence results. Nor did the presence of comorbid psychiatric disorders.

Boedhoe et al. (2020) recently took this ENIGMA work forward by directly comparing ADHD, autism and Obsessive-Compulsive Disorder (OCD). Structural T1-weighted whole-brain MRI data were analysed in each site, using Freesurfer software and standardised processing protocols, to pool measures from each cohort without the need for raw data transfer. The data set comprised no fewer than 5827 healthy controls, 2271 patients with ADHD, 1777 with autism and 2323 with OCD, from 151 cohorts worldwide. Interesting trends emerged but no significant differences between disorders survived correction for multiple comparisons.

It should however be noted that neuroimaging studies and reviews using different methods may arrive at different results. Voxel-based morphometry (VBM), for example, measures density or volume at a voxel level and meta-analyses tend to use a ‘signed differential mapping’ procedure to pool study results (which increases power but can be prone to false positives). One such meta-analysis of structural and functional MRI studies showed, for example, that ADHD and OCD have possibly disorder-specific structural and functional alterations in basal ganglia and insula – reductions in ADHD but increases in OCD relative to controls. The same was true in frontal regions, in that rostro-dorsal medial frontal regions were decreased in structure and function in OCD but ventrolateral prefrontal regions were under-functioning in ADHD (Norman et al. 2016).

What is missing, however, is a clear demonstration of how these imaging features map on to key cognitive characteristics or symptoms of ADHD or other developmental disorders (Philip et al. 2012). There is some evidence that structural and functional abnormalities in the amygdala are just as evident, if not more so, in ODD/CD as compared to ADHD, and that the most consistent clinical association is with ODD/CD symptoms (Noordermeer et al. 2016). Comparing studies of the the two groups of patients, Puiu et al. (2018) found that they share similar cortico-limbic structural and functional alterations but differential associations. In ADHD, Impulsive Aggression (IA) was associated with prefrontal cortex (PFC) and cingulate activity, while Response Inhibition (RI) deficits were linked to hypoactivity in the dorso/ventro-lateral PFC, insula, and striatum. Across disorders, cortico-limbic dysfunctions underlied IA, while RI was mostly associated with aberrant PFC activity. Importantly, there is fairly consistent evidence that methylphenidate normalises these patterns in ADHD. A fMRI meta-analysis showed that methylphenidate significantly enhanced activation in bilateral inferior frontal cortex/insula during inhibition and time discrimination but had no effect on working memory networks (14 fMRI datasets, 212 children with ADHD). A more lenient threshold also revealed increased putamen activation (Rubia et al. 2014).

Focussing on the amygdala in ADHD, Van Dessel et al (2019) build on their previous findings with fMRI that amygdala dysfunction is associated with delay aversion in ADHD. In a careful combined structural and functional MRI study of 28 adolescents aged 10–18 with ADHD (three with ODD, none with CD) and 32 matched controls, reduced amygdala volumes (maximal in the area responsible for emotional processing) were associated with and indeed mediated delay related amygdala hyperactivity (maximal basolaterally, involved in stress response) with both objective delay-related stimuli processing and subjective delay aversion. Most of the patients (24) were medicated but withdrawn from treatment 72 hours before scanning, making the effects of medication unclear. Symptom severity was not examined but one wonders if the delay aversion described is related to emotional liability, stress intolerance or impulsivity. Perhaps there is an ADHD subgroup with pronounced amygdala disruption at high risk of aggression and violence.
Connectivity and correlates

It is of course clear that most thoughts and actions require co-ordinated activity across neural systems, but methodological complications and variation between labs has hindered the development of consensus. Diffusion (Tensor) Imaging (DTI) is the standard approach to examining structural connectivity in the brain, but voxel-based and tract-based analyses have delivered little agreement as to which regions are most affected. There is a general tendency to finding reduced connectivity in ADHD but even this is inconsistent in studies which have gone to the trouble to confirm that motion in the scanner could not account for the results (Aoki et al. 2018).

Resting-state fMRI is the most commonly used approach to study functional connectivity in the brain. The default-mode network (DMN) reflects a set of interacting brain regions (i.e. medial prefrontal cortex, precuneus, posterior cingulate cortex (PCC), and medial temporal regions) with coherent neural activation when internal thoughts are self-generated, and higher activity at rest than when performing externally focussed goal-directed tasks (Raichle et al. 2001).

Sutcubasi et al. (2020) have conducted a very useful meta-analysis of 20 seed based resting state functional connectivity studies in 944 (mainly treated) patients with ADHD and 1121 controls. They found reduced connectivity within the core DMN sub-system (from a PCC seed), alongside increases in a broad set of nodes in systems involved in cognition and motivation, especially in children and adolescents. DMN overactivity at rest and/or underactivity on activation is however a common observation in many psychiatric disorders, but DMN dysfunction could have differential clinical associations – such as with mind-wandering and inattention in ADHD, and perhaps anxious rumination in OCD.

Li et al. (2020) show DMN overactivity in OCD (N = 42, mean age 27 years) compared to healthy controls, with increased hippocampal connectivity to fronto-temporal regions showing different sub-regional associations with obsessive, compulsive and anxious symptom severity scores. Hippocampal functional connectivity to left middle temporal gyrus correlated with obsessions and anxiety, and a mediation analysis showed that this mediated the relationship between obsessions and anxiety. This could perhaps reflect a difficulty in using the regularities of previous experience to regulate anxiety.

Almost all ADHD treatment studies suggest that methyphenidate normalises DMN circuits (Santos et al. 2019), just as many treatments in psychiatry may also do. Woelfer et al. (2019) conducted a randomised placebo-controlled study of the effects of ketamine on functional connectivity in 53 healthy participants. They found that Brain-Derived Neurotrophic Factor (BDNF) plasma levels increased and seemed to drive ketamine induced decreases in resting-state functional connectivity between PCC and ventro-medial PFC. BDNF is a neurotrophin involved in neurogenesis and synaptic plasticity, especially in the hippocampus, and has been implicated in the pathophysiology of several neuropsychiatric disorders. Plasma BDNF and its common genetic polymorphisms are not consistently abnormal in ADHD but some specific haplotypes or polymorphisms may be (Bonvicini et al. 2018). Given that ketamine increases synaptic plasticity, and has recently been licenced for the treatment of treatment resistant depression, its mode of action may include normalising resting state functional connectivity and this may be a way of targeting its use in depression and other psychiatric disorders.
Conclusions

ADHD, autism, ODD/CD and OCD are common neurodevelopmental disorders that frequently co-occur but are usually distinguishable clinically. Given the overlap in genetic and environmental risk factors – some of which have known impact on brain imaging measures – some overlap in neuroimaging findings across the disorders is to be expected. There may not be specific neuroimaging phenotypes, but there may well be differential associations between disrupted anatomy and function, potentially mediating cognitive processes such as deficits in frontal inhibition and social cognition, and symptoms of the conditions. A transdiagnostic approach is worth pursuing alongside disorder specific studies, but ADHD has a specific treatment that can transform lives and has clear effects on functional MRI. A refined translational neuroimaging of ADHD and related developmental disorders will however require a concerted attempt to address these issues across multiple laboratories using compatible methodologies.

Frequency: Yearly ISSN: 1562-2975 eISSN: 1814-1412 https://www.tandfonline.com/doi/abs/10.1080/15622975.2020.1823694

13/11/2020

Issue 8 is available here: https://www.tandfonline.com/toc/iwbp20/21/8?nav=tocList
Dear colleagues,

It is my great pleasure to introduce to you the eighth issue of 2020 featuring original research on depression, drug–drug interaction in psychiatric treatment of HIV, cannabinoid treatment of tardive dyskinesia, treatment of concurrent abuse of co***ne/ni****ne and a review article on management of mild cognitive impairment (MCI).

Reduction of circulating brain-derived neurotrophic factor (BDNF) levels and increase of plasma dipeptidyl peptidase-4 (DPP4) activity have both been reported to link to the pathogenesis of depression. Zheng and colleagues explored the correlation between the ratio DPP4 activity/BDNF levels (DBR) and depressive symptoms as a biomarker for depression. In general, DPP4 activity was negatively correlated to BDNF levels in participants with and without depression. Depressed patients had lower levels of BDNF and higher DPP4 activity and DBR in peripheral circulation when compared with controls. The results suggested that the positive correlation between DBR and depressive symptoms identify DBR as a novel biological marker or a possible therapeutic target for depression.

Lee et al. found that detection of intracellular cytokines after lipopolysaccharide (LPS) stimulation of monocytes in vitro rather than simple measurement of circulating cytokines may be more sensitive correlates of subthreshold depressive symptoms. Circulating inflammatory markers have been correlated with mood disorders, but often no changes are found in case-control studies (Mucci et al. 2020). They measured plasma tumour necrosis factor-α (TNF- α), interleukin-6 (IL-6) and C-reactive protein (CRP), and in vitro LPS-induced monocyte production of IL-6 and TNF- α, in 117 participants to a cross-sectional insomnia study in a healthy community-dwelling older adults. Multivariate linear regression was conducted to test the associations between inflammatory markers and subthreshold depressive symptoms in the entire sample, as well as in subgroups stratified into higher and lower inflammation levels. In the entire sample, no circulating biomarkers were significantly associated with subthreshold depressive symptoms. Instead, LPS-induced cytokines significantly and positively correlated with subthreshold depressive symptoms in higher inflammation subgroups. The authors concluded that LPS-induced cytokines may be more sensitive correlates of subthreshold depressive symptoms than circulating cytokines, particularly in older adults with higher systemic inflammation.

The management of psychiatric illness in HIV-infected patients is clinically challenging because of the risk of potential drug–drug interactions. Cattaneo and associates aimed to measure the anti- depressant and/or antipsychotic drug concentrations in HIV-infected patients during routine outpatient visits. Six hundred HIV-infected patients were screened during the first 15 months after the introduction of outpatient polytherapy management service. The distribution of psychotropic drug concentrations in HIV-infected patients was compared with that observed in a control group of HIV-negative patients monitored over the same period. Fifty-five per cent of patients receiving concomitant antiretroviral and psychotropic drug treatment had plasma psychotropic drug concentrations that were below minimum effective levels, compared to 26% of HIV-negative patients. The results were not affected by patients’ gender, age, adherence to therapies or drug–drug interactions and showed that psychotropic drug treatments are associated with a higher rate of subtherapeutic concentrations in HIV-infected patients. The possible reasons for this finding in HIV-infected patients are analysed.

Lateral habenula (LHb) is a key brain structure for mediating behavioural responses to aversive stimuli and recently hyperactivation of this area has been involved in pathophysiology of depression (Cui et al. 2018). LHb receives presynaptic inputs from ventral pallidum (VP) which relates to reward, motivation and hedonics. Liu and colleagues investigated the role of glutamatergic VP-LHb projections in negative emotions and depressive-like behaviour, using optogenetic manipulation in mice. Activation of VP-LHb glutamatergic projections induced aversive behaviour in the real time place aversion test. In mice subjected to chronic social defeat stress (a stress protocol used to induce depressive/anxious-like behaviour), optogenetic activation of this circuit induced depressive-like phenotype, while inhibition of the circuit exerted antidepressant effect in social stress susceptible mice. Local injection of ketamine into LHb rescued the depressive-like phenotype caused by activation of this circuit. The results of the study demonstrated an involvement of the glutamatergic VP-LHb circuit in stress-induced depression-related behaviours and in the antidepressant action of ketamine.

Movement disorders, such as tardive dyskinesia (TD), are associated not only with typical and atypical antipsychotics, but also with levodopa treatment, although they are more common in patients on typical antipsychotics. Kajero and associates investigated the effects of oral cannabidiol (CBD; the most abundant non-psychotomimetic compound in Cannabis, which has raised much interest for its putative therapeutic actions in CNS; Khoury et al. 2019) on TD. They assessed haloperidol-induced vacuous chewing movements (VCM) in rats, an animal model of TD. Rats were administered haloperidol only or haloperidol + CBD at various doses between 3 and 10 mg/kg. The results showed that CBD co-administration with haloperidol at different doses attenuated the VCMs and increased motor tone produced by haloperidol. CBD also ameliorated haloperidol-induced increased blood glucose levels. CBD alone at 5 mg/kg showed anxiolytic properties. This work confirmed that CBD can ameliorate motor impairments produced by haloperidol. The data suggest that CBD could be combined with haloperidol to prevent the emergence of extrapyramidal side effects and long-term movement disorders, such as acute dystonic disorder and TD.

The review by Kasper et al. addresses the issue of management of mild cognitive impairment (MCI). The authors aim to describe the concept of MCI with regard to diagnosis, pathogenesis and treatment, review the evidence of available pharmacological and non-pharmacological treatments for MCI, and analyse respective information and limitations in national and international guidelines. Consensus diagnostic criteria for MCI are available; early recognition and accurate classification of MCI subtypes is possible. Operational use of biomarkers for amyloid pathology and neuronal injury allows to differentially assess the likelihood of progression to Alzheimer’s disease (AD) dementia at the MCI stage, including cerebrospinal fluid concentrations of amyloid beta 42, phospho-tau/total tau protein, and several blood-based biomarkers (Lewczuk et al. 2018). Mixed pathologies are the rule in MCI, thus a multi-target treatment approach is a rational strategy. Promising evidence has been generated for multi-domain interventions. Limited evidence is available for different pharmacological classes that have been investigated in MCI clinical trials (e.g. acetylcholinesterase inhibitors). EGb 761VR treatment improved symptoms in some clinical trials and is currently the only pharmacological treatment recommended in existing guidelines for the symptomatic treatment of MCI. Recent national guidelines are only just beginning to consider pharmacological and non-pharmacological treatment options for patients with MCI. However, recommendations reported in international and national dementia guidelines are inconsistent and do not consider the recent diagnostic concepts, nor the most recent pharmacological and non-pharmacological treatment evidence. The role of biomarkers as a tool for diagnosing the MCI stage of AD is not considered; and treatment outcomes in MCI only focus on the lack of risk reduction for progression to dementia. In order to improve management of MCI and recognise the importance of this disease stage within the AD continuum, it is necessary to update existing guidelines with respect to available evidence.

Barbosa-Mendez and colleagues assessed the use of mirtazapine to reduce the reinforcing effects of concurrent use of co***ne and ni****ne. Concurrent abuse of co***ne and ni****ne is considered a public health problem, but no effective therapy is available. Mirtazapine is an antagonist of the α2-adrenoceptor and 5-HT2A/C and 5-HT3 receptors, and has been shown to reduce co***ne, ni****ne and methamphetamine behavioural effects in humans and animals. The study evaluated the effect of mirtazapine on the enhancement of locomotor activity during the induction and expression of co***ne and ni****ne-dependent locomotor sensitisation. Wistar rats were dosed with co***ne, ni****ne or co***ne + ni****ne combination. Mirtazapine was administered during the extinction phase. Mirtazapine decreased co***ne + ni****ne-induced locomotor activity and induction and expression of locomotor sensitisation. In addition, co-administration of mecamylamine and mirtazapine significantly enhanced the effect of mirtazapine. The result suggest that mirtazapine shows efficacy in decreasing the psycho-stimulant effects of concurrent use of co***ne and ni****ne.
Yours sincerely,
Maurizio Popoli , PhD
Field Editor

Frequency: Yearly ISSN: 1562-2975 eISSN: 1814-1412 https://www.tandfonline.com/doi/abs/10.1080/15622975.2020.1823693

13/11/2020

Issue 7 is now available online: https://www.tandfonline.com/toc/iwbp20/21/7?nav=tocList
In the second decade of the twenty-first century, there has been an eruption of studies on the pathogenic role of stress in early life, named also ‘early life adversity’ or ‘childhood trauma’, in psychiatric disorders. Many such papers have been published in our journal in recent years and this topic was also reflected in most of the articles of the seventh issue 2020.

In their review of the epigenetic alterations associated with childhood trauma in relation to adult mental health outcomes, Nöthling et al. (2020) point to the role of the epigenetic processes among which methylation is the most important. The genes mainly influenced by the inappropriate methylation include the glucocorticoid receptor NR3C1 gene, serotonin transporter SLC6A4 gene, brain-derived neurotrophic factor BDNF gene, oxytocin receptor OXTR gene, and FK 506 binding protein FKBP5 gene. All these genes were found significant in the mechanisms of childhood trauma (Jaworska-Andryszewska and Rybakowski 2019) and will be repeatedly mentioned in the further parts of the editorial. The authors argue that epigenetic modification is most important for translating the early life stress into psychiatric disorders of adult life. Such importance was confirmed, among others, by Russian researchers in relation to chronic physical aggression (Chistiakov and Chekhonin 2019).

Womersley et al. (2020) studied a mediation between childhood emotional neglect and changes in brain structures due to the oxytocin receptor gene (OXTR) variants. They showed that the rs2254298 A risk allele of the OXTR gene was independently associated with reduced left hippocampal volume and reduced bilateral amygdala volumes. Earlier, Schiele et al. (2018) found that this polymorphism of the OXTR gene was associated with an interaction between behavioural inhibition and separation anxiety in vulnerability for complicated grief. Furthermore, Monteleone et al. (2019) confirmed the effect of childhood trauma on brain structures.

The Irish investigators (Jairaj et al. 2020) assessed the hypothalamic-pituitary-adrenal (HPA) axis function in the perinatal period in relation to major depressive disorder and early life adversity (ELA). They found that a history of ELA regardless of comorbid depression was associated with higher evening cortisol levels during pregnancy. They postulated that this phenomenon may be connected with a higher risk of both antenatal and postpartum depression.

The biomarkers in pregnancy were also a topic of the paper by Levitan et al. (2020). They investigated plasma tryptophan and kynurenine concentrations in pregnant women depending on a history of full or subsyndromal seasonal affective disorder. The paper marks more than half a century of the kynurenine hypothesis of depression (Lapin and Oxenkrug 1969). The authors found significant differences in both these substances related to maternal seasonality and season of conception. These findings may have implications for risk of depression in pregnancy and also for foetal brain development.

Labad et al. (2020) studied the HPA function and cannabis use in recent-onset psychosis in relation to childhood trauma and stressful life events. They found that cannabis use was associated with a more flattened diurnal cortisol slope independent of recent-onset psychosis diagnosis. However, no relationship was found with childhood trauma and stressful life events.

Kleine Deters et al. (2020) in an international study assessed executive functioning and emotion recognition in young patients, aged 8–18 years with the oppositional defiant disorder (ODD) and/or conduct disorder (CD) compared with healthy subjects of this age. They found that visual working memory and inhibitory control were impaired in both conditions. However, these deficits were not explained by comorbid attention-deficit/hyperactivity disorder (ADHD) or internalising symptoms. These findings challenge the view that neuropsychological impairments in youth with ODD/CD are driven by comorbid ADHD and suggest distinct neurocognitive mechanisms.

In the era of Covid-19 pandemics, the paper on this topic should not be missing. This claim was fulfilled by the report of the German authors (Schmidt and Rein 2020) on the novel treatment targets for Covid-19. According to them, such a target could be a stress protein, FK 506 binding protein, associated with various mental disorders such as major depression and post-traumatic stress disorder (PTSD). They suggest that this protein could modify the neuroinvasive potential of the SARS-CoV-2 virus. The reader of this editorial may recall that the gene for this protein (FKBP5) was mentioned at the beginning of the article as instrumental for the effects of early life stress. A recent example of the role of the FKBP5 gene in the sequels of childhood abuse is the results of the paper of Tamman et al. (2019). The authors found that the polymorphism of this gene may predict the risk for PTSD exerted by the childhood abuse and that attachment style may moderate this effect.

12/10/2020

New issue alert! Issue 6 is now available here:https://www.tandfonline.com/toc/iwbp20/21/6?nav=tocList featuring the WFSBP Treatment Guidelines for the pharmacological treatment of paraphilic disorders: https://www.tandfonline.com/doi/full/10.1080/15622975.2020.1744723 with a special Commentary by Dr. Krueger: https://www.tandfonline.com/doi/full/10.1080/15622975.2020.1823686

(2020). Commentary on guidelines for the pharmacological treatment of paraphilic disorders. The World Journal of Biological Psychiatry: Vol. 21, No. 6, pp. 409-411.

22/04/2020

Call for Symposia and Workshops for the 15th World Congress of Biological Psychiatry in Vienna. Further information found here:

Abstracts for symposia or workshops can now be submitted for the 15th World Congress of Biological Psychiatry in Vienna.

22/04/2020

New issue alert! Issue 1 is now available here: https://www.tandfonline.com/toc/iwbp20/current
Featuring research on schizophrenia:

Dear colleagues,

It is my great pleasure to introduce to you the first issue of 2020 featuring original research on schizophrenia.

Pierson and colleagues review the biology and neurotropy of the Zika virus in relation to the hypothesis of neurotropic in utero infections in schizophrenia. Zika virus has been associated with a wide variety of neural tube and neuroanatomical abnormalities. The authors argue that the recent outbreak in the Western Hemisphere opens up the opportunity to investigate the congenital infection theory of the pathogenesis of schizophrenia. https://www.tandfonline.com/doi/full/10.1080/15622975.2018.1500027

Joob and Wiwanitkit comment on the article by Pierson et al. They state that in Southeast Asia, the Zika virus is common, however, is not associated with congenital anomalies. Interestingly, although, a high rate of asymptomatic immunoreactivity has been reported in Cambodia, there are no reports on the association between infection and schizophrenia or on increased incidence of schizophrenia. https://www.tandfonline.com/doi/full/10.1080/15622975.2018.1533995

Schoonover and associates determined the dysbindin and copper transporter protein expression as well as copper content in schizophrenia. In the copper-rich substantia nigra, schizophrenia patients had an altered isoform expression of copper transporters and dysbindin as well as a decreased copper content. These results show interrupted copper transport in schizophrenia that occurs in copper-deficient state. In addition, the copper homeostasis may further be regulated by dysbindin. https://www.tandfonline.com/doi/full/10.1080/15622975.2018.1523562

Djordjevic et al., examined the effect of cigarette smoking and heavy coffee consumption on the efficacy and safety of olanzapine treatment in schizophrenia in association to variants in cytochromes P450 genes. Being CYP1A2*1F allele carrier was associated with decreased efficacy and increased safety of olanzapine treatment. Treatment outcome was additionally affected by dosage, s*x, age and CYP2D6 metabolizer status. https://www.tandfonline.com/doi/full/10.1080/15622975.2018.1548779

Nani and colleagues assessed the angiotensin I-converting enzyme (ACE) activity in an animal model of schizophrenia. Dopaminergic manipulation with antipsychotics and psychostimulants changed the activity of ACE without any correlation to blood pressure. Their findings strengthen the usefulness of this animal model for the investigation of several aspects of schizophrenia. https://www.tandfonline.com/doi/full/10.1080/15622975.2019.1583372

Khan et al., investigated the relationship between the mortality rates of depression and schizophrenia in comparison to hypertension and diabetes. Psychiatric conditions had higher all-cause mortality rates compared to chronic medical conditions, even with the exclusion of suicides. Clinical trials should investigate the impact of investigational medications on the mortality associated with these conditions. https://www.tandfonline.com/doi/full/10.1080/15622975.2018.1514465

n a brief report, Boiko and colleagues test the association between muscarinic receptor gene polymorphisms and tardive dyskinesia (TD) in schizophrenia. The prevalence of a specific genotype of the CHRM2 gene was lower in tardive dyskinesia patients suggesting a protective effect for the development of TD. However, these results should be interpreted with caution, as they did not reach significance after including covariates such as age and gender. https://www.tandfonline.com/doi/full/10.1080/15622975.2018.1548780

Yours sincerely,
Dan Rujescu, MD
Chief Editor